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Mecanismos y inhibición de la acilación de Wnt mediada por Porcupine
Yang Liu1, Xiaofeng Qi1, Linda Donnelly1
1Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature
|July 13, 2022
Resumen
Este estudio revela el mecanismo de modificación de la proteína Wnt por el puercoespín (PORCN), crucial para la señalización de Wnt. Las estructuras muestran cómo LGK974, un medicamento contra el cáncer, inhibe PORCN al bloquear el acceso al sustrato, ayudando al desarrollo del tratamiento contra el cáncer.
Área de la Ciencia:
- La bioquímica
- Biología estructural
- Biología molecular
Sus antecedentes:
- La señalización Wnt es vital para el desarrollo embrionario y la homeostasis tisular.
- La señalización aberrante de Wnt está relacionada con varios tipos de cáncer.
- La señalización Wnt requiere palmitoleolación por el puercoespín (PORCN).
Objetivo del estudio:
- Elucidar el mecanismo estructural de la palmitoleolación de la proteína Wnt por el PORCN.
- Comprender el mecanismo de inhibición de PORCN por el fármaco contra el cáncer LGK974.
- Proporcionar información para el desarrollo de nuevos inhibidores de PORCN para el tratamiento del cáncer.
Principales métodos:
- Se utilizó la crio-microscopía electrónica (cryo-EM) para determinar cuatro estructuras de alta resolución del PORCN humano.
- Se obtuvieron estructuras para el PORCN complejado con palmitoleoil-CoA, LGK974, WNT3A hairpin 2 (WNT3Ap) y un análogo de WNT3Ap.
Principales resultados:
- Las estructuras revelan la inserción de WNT3A hairpin 2 en PORCN desde el lado lumenal y el acceso de palmitoleoyl-CoA desde el lado citosólico.
- La histidina catalítica facilita la transferencia del grupo palmitoleoil a la horquilla Wnt 2.
- LGK974 inhibe el PORCN al unirse al sitio de palmitoleoil-CoA, impidiendo el acceso al sustrato.
Conclusiones:
- Este trabajo proporciona una comprensión mecanicista detallada de la acilación de Wnt por PORCN.
- Los hallazgos avanzan en el desarrollo de inhibidores de PORCN como una estrategia terapéutica para los cánceres impulsados por la señalización aberrante de Wnt.
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